Schizophrenia Tied To Abnormal Memory Network In Brain

Individuals suffering with schizophrenia are subject to a whole host of disturbing, life-changing symptoms. They can range from disorganized thinking and an inability to plan for the future to full-on hallucinations and paranoid delusions. Through treatment with psychiatric therapy and medication can be effective for some, the psychiatric disease has largely remained a medical mystery.

However, researchers at the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory at MIT have uncovered what they term “a faulty brain mechanism” they believe is crucial in the eventual development of schizophrenia and other psychiatric disorders in humans.

Speaking about the study published in today’s issue of Neuron, Susumu Tonegawa, director at RIKEN-MIT said, “Our study provides new insight into what underlies schizophrenia’s disordered thinking and zeroes in on a new target for future investigation into the neural basis of a cognitive disorder that affects more than 1 percent of the world’s population.” Tonegawa is also a senior author of the study.

This study, like many others in the fields of genetics, was an animal study. The team employed the use of genetically engineered mice that displayed symptoms of schizophrenia. One difficulty faced by this study, in particular, was figuring out how to model the complex nature of disorganized thought in the mice.

The research team began their study with the understanding that human patients suffering from cognitive disorders will present abnormal neural activity in what is known as the default mode network (DMN). The DMN is a network inclusive of the brain’s prefrontal cortex and the hippocampus. It is in these areas of the brain scientists believe we process memories.

As the researchers pointed out, because the DMN is involved in recall and the planning of future actions, understanding how it processes information and interacts with other brain areas could help to explain how brain disorders come about when this network is faulty.

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The genetically modified mice carried a gene mutation that also exists in some sufferers of schizophrenia. More specifically, the mutation entailed the absence of the normal gene for an enzyme known as calcineurin. Calcineurin is critical in creating the synaptic plasticity that is used in learning and memory.

This specific genetically modified mouse was first created some 10 years ago by Tonegawa. He first noted that these mice displayed several of the behavioral symptoms of schizophrenia, like short-term memory impairment, attention deficits and abnormal social behavior.

The non-modified mouse brain goes into a resting state after running a maze, allowing the brain to process the information related to the maze experience. As an example, if you’ve ever played a puzzle game like Tetris or Sudoku, you might find after putting it down you are still playing the game in your mind. This style of information processing is indicative of normal brain function.

However, in the modified mouse brain, the team found the exact opposite occurs. Rather than going into a resting state, electrical activity in the hippocampus actually surged.

“Our study demonstrated an increase in neural activity in the hippocampus during awake resting periods,” said study co-author Junghyup Suh. “More important, we demonstrated – for the first time – disrupted information processing in single cells as well as neural circuits.”

During its maze run, the non-modified mouse brain will fire off neurons in the hippocampus at key locations within the maze. These are known as place fields. Once out of the maze, the normal brain will replay these place fields in specific order during rest periods. This aids in building memory which allows the mouse to move through the maze faster the next time around.

This action, however, did not occur in the same way in the brains of genetically modified mice. The place cells, while collected during the maze run, were seemingly reactivated during the rest period in no discernible order. In fact, the place cells were reactivated at an abnormally high level and almost simultaneously.

“We think that in this mouse model, we may have some kind of indication that there’s a disorganized thinking process going on,” said Suh, a research scientist at the Picower Institute. “During ripple events in normal mice we know there is a sequential replay event. This mutant mouse doesn’t seem to have that kind of replay of a previous experience.”

“Our study provides a novel way to look into the actions of current drugs and treatments and may lead to new insights for improved treatment of psychiatric disorders,” Suh said.

Further studies of these mice could help reveal more about the role of the default mode network in schizophrenia, Tonegawa says.